A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment.
A triplet repeat expansion genetic mouse model of infantile spasms syndrome, Arx(GCG)10+7, with interneuronopathy, spasms in infancy, persistent seizures, and adult cognitive and behavioral impairment.
复制标题
婴儿痉挛综合征 Arx(GCG)10+7 的三联体重复扩增遗传小鼠模型，伴有神经元病、婴儿期痉挛、持续性癫痫发作以及成人认知和行为障碍。
DOI：
10.1523/jneurosci.0915-09.2009
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发表时间：
2009-07-08
影响因子：
5.3
通讯作者：
Noebels, Jeffrey L.
中科院分区：
文献类型：
--
作者：
Price, Maureen G.;Yoo, Jong W.;Burgess, Daniel L.;Deng, Fang;Hrachovy, Richard A.;Frost, James D., Jr.;Noebels, Jeffrey L.
婴儿痉挛综合征（ISS）是一种灾难性的小儿癫痫，伴有运动痉挛、持续性癫痫发作、智力迟钝，在某些情况下还伴有自闭症。其单基因原因之一是X染色体上的插入突变（c.304ins（GCG）7），将神经元间特异性转录因子ARX的第一个多聚丙氨酸区从16个丙氨酸密码子扩展到23个丙氨酸密码子。Arx基因的突变损害GABA和胆碱能神经元间的迁移，但在新生儿致死表型的结果。我们开发了ISS的第一个可行的遗传小鼠模型，该模型自发地再现了人类三重重复扩增突变的显著表型特征。Arx（GCG）10+7（“Arx Plus7”）幼仔显示异常痉挛样肌阵挛和其他关键EEG特征，包括多灶性棘波、电递减发作和持续至成熟期的自发性癫痫发作。Arx突变体的神经行为特征显著降低焦虑，受损的联想学习和异常的社会互动。Arx+皮质中间神经元的层状减少以及新皮质层和海马中钙结合蛋白表达的中间神经元的选择性减少，而不是小清蛋白或钙视蛋白表达的中间神经元的选择性减少表明，成年前脑中缺少特定类别的突触抑制，这为癫痫发作和认知障碍提供了基础。突变纹状体中钙结合蛋白、NPY表达和胆碱能中间神经元的显著减少表明，该网络中的神经功能障碍可能导致运动障碍性运动痉挛。这种小鼠模型缩小了大脑抑制网络中关键致病因素的范围，这些因素对重现这种复杂的神经发育综合征至关重要。
Infantile spasms syndrome (ISS) is a catastrophic pediatric epilepsy with motor spasms, persistent seizures, mental retardation, and in some cases, autism. One of its monogenic causes is an insertion mutation (c.304ins (GCG)7) on the X chromosome, expanding the first polyalanine tract of the interneuron-specific transcription factor ARX from 16 to 23 alanine codons. Null mutation of the Arx gene impairs GABA- and cholinergic interneuronal migration but results in a neonatal lethal phenotype. We developed the first viable genetic mouse model of ISS that spontaneously recapitulates salient phenotypic features of the human triplet-repeat expansion mutation. Arx (GCG)10+7 (“Arx Plus7”) pups display abnormal spasm-like myoclonus and other key EEG features, including multifocal spikes, electrodecremental episodes, and spontaneous seizures persisting into maturity. The neurobehavioral profile of Arx mutants was remarkable for lowered anxiety, impaired associative learning, and abnormal social interaction. Laminar decreases of Arx+ cortical interneurons and a selective reduction of calbindin-, but not parvalbumin- or calretinin-expressing interneurons in neocortical layers and hippocampus indicate that specific classes of synaptic inhibition are missing from the adult forebrain, providing a basis for the seizures and cognitive disorder. A significant reduction of calbindin, NPY-expressing and cholinergic interneurons in the mutant striatum suggest that dysinhibition within this network may contribute to the dyskinetic motor spasms. This mouse model narrows the range of critical pathogenic elements within brain inhibitory networks essential to recreate this complex neurodevelopmental syndrome.